Insulin-dependent diabetes mellitus (IDDM), generally synonymous with type 1 diabetes, is the classical, life-threatening form of diabetes, the treatment of which was revolutionized by the discovery of insulin in 1922. The prevalence of type 1 diabetes is unfortunately widespread throughout much of the world and hence type 1 diabetes represents a serious condition with a significant drain on health resources.
The etiology of type 1 diabetes is multifactorial and not yet entirely clear. However it is characterised by a partial or complete autoimmune destruction of the pancreatic beta cells. In the acute phase of type 1 diabetes insulin deficiency is thus the dominating pathophysiological feature.
After starting insulin treatment many patients enjoy good blood glucose control with only small doses of insulin. There is an early phase, the “honeymoon period”, which may last a few months to a year and which probably reflects a partial recovery of beta cell function. This is, however, a temporary stage and ultimately, the progressive destruction of the beta cells leads to complete cessation of insulin secretion and increasing requirements for exogenous insulin.
While the short term effects of hypoinsulinemia in the acute phase of type 1 diabetes can be well controlled by insulin administration, the long term natural history of type 1 diabetes is darkened by the appearance in many patients of potentially serious complications known as late, or late onset complications. These include the specifically diabetic problems of nephropathy, retinopathy and neuropathy. These conditions are often referred to as microvascular complications even though microvascular alterations are not the only cause. Atherosclerotic disease of the large arteries, particularly the coronary arteries and the arteries of the lower extremities, may also occur.
Nephropathy develops in approximately 35% of, type 1 diabetes patients, particularly in male patients and in those with onset of the disease before the age of 15 years. Diabetic nephropathy is characterized by persistent albuminuria secondary to glomerular capillary damage, a progressive reduction of the glomerular filtration rate and eventually, end stage renal failure requiring dialysis treatment or kidney transplantation.
The prevalence of diabetic retinopathy is highest among young-onset type 1 diabetes patients and it increases with the duration of the disease. Proliferative retinopathy is generally present in about 25% of the patients after 15 years duration and in over 50% after 20 years. The earliest lesion of diabetic retinopathy is a thickening of the capillary basement membrane, followed by capillary dilation and leakage and formation of microaneurysms. Subsequently, occlusion of retinal vessels occurs resulting in hypoperfusion of parts of the retina, oedema, bleeding and formation of new vessels as well as progressive loss of vision.
The diabetes-induced nerve disorder is most often a distal symmetric primarily sensory neuropathy affecting 30-50% of type 1 patients. It is often associated with autonomic dysfunction. Sensory neuropathy may cause loss of sensation, appearance of paraaestesia or numbness or, alternatively, result in unpleasant sensations, sometimes pain, in the legs, feet or hands. The morphological changes of diabetic peripheral neuropathy include distal axonal loss with a reduction of the number of large (myelinated) and small fibers, focal demyelinisation and regenerating activity. The function abnormalities include slowing of nerve conduction velocities, reduction of nerve signal amplitudes and rises in sensory modality thresholds. Autonomic neuropathy afflicts approximately 50% of the patients with type 1 diabetes of more than 15 years duration. It may evolve through defects in thermoregulation, impotence and bladder dysfunction followed by cardiovascular reflex abnormalities. Late manifestations may include generalized sweating disorders, postural hypotension, gastrointestinal problems and reduced awareness of hypoglycemia. The latter symptom has grave clinical implications.
A number of theories have been advanced with regard to possible mechanism(s) involved in the pathogenesis of the different diabetic complications but this has not yet been fully elucidated. Metabolic factors may be of importance and it has been shown that good metabolic control is accompanied by significantly reduced incidence of complications of all types. Nevertheless, after 7-10 years of good metabolic control, as many as 15-25% of the patients show signs of beginning nephropathy, 10-25% have symptoms of retinopathy and 15-20% show delayed nerve conduction velocity indicating neuropathy. With longer duration of the disease the incidence of complications increases further. There is thus a significant clinical need for the control and management of these diabetic complications.
In addition to IDDM (type I diabetes), other types of diabetes are known. Diabetes mellitus is the chronic syndrome of impaired carbohydrate, protein and fat metabolism owing to insufficient secretion of insulin or to target tissue insulin resistance. It occurs in two major forms, type I as discussed above, and type II, non-insulin dependent diabetes mellitus, which differs in etiology, pathology, genetics, age of onset and treatment. Generally, there is no requirement for exogenous insulin in the treatment of type II diabetes. Other forms of diabetes, beyond diabetes mellitus, also exist. Whilst complications, e.g. micro angiopathic complications affecting the retinas and kidneys are seen with higher incidence in type I diabetes, it is not precluded that complications, including those which occur in type I, may occur also with type II diabetes, and other forms of diabetes.
Proinsulin C-peptide is a part of the proinsulin molecule which, in turn, is a precursor to insulin formed in the beta cells of the pancreas. For a long time it was believed that C-peptide (known variously as C-peptide or proinsulin C-peptide) had no role other than as a structural component of proinsulin, facilitating correct folding of the insulin part. However, it has in more recent years been recognised that C-peptide has a physiological role as a hormone in its own right (Wahren et al., (2000), Am. J. Physiol. Endocrinol. Metab, 278, E759-E768). In diabetic patients, it alleviates renal dysfunction, improves blood flow in several tissues, ameliorates nerve functional impairments and is believed to delay or prevent the onset of late complications (Wahren et al., (2000) supra; Johansson J et al. Biochem Biophysical Research Comm. 2002; 295:1035-1040; Wahren et al. in International Textbook of Diabetes, 3rd Edition, editors DeFronzo, Ferrannini, Keen and Zimmet, 2004, Wiley, London). Indeed, C-peptide has been proposed for use in the treatment of diabetes in EP 132769 and in SE460334 for use in combination with insulin in the treatment of diabetes and prevention of diabetic complications.
C-peptide is known to have a relatively short half-life. In humans the half-life is approximately 30 minutes and a dose of C-peptide injected into a rat would be expected to have disappeared entirely from circulation within 2-3 hours. Due to the short half-life of C-peptide, in all prior art disclosures several daily doses (typically 3 or 4) or a continuously administered dose are used to treat diabetes or diabetic complications. For example, Sima et al. (Diabetologia, 44, 889-897, 2001) administered C-peptide in a continuous dose by osmopump to diabetic rats. In one known case Ido et al. (Science, 277, 563-566, 1997) administered C-peptide (at 130 nmol per kilogram of bodyweight) twice daily to rats with streptozotocin-induced diabetes. However, in this study human C-peptide was given to rats in a dose approximately five fold per kg body weight higher than otherwise used. Human C-peptide can be expected to be catabolized more slowly in the rat than the homologous C-peptide, which together with the high dosage may account for the observed effect in this study.
Similarly, insulin, which is derived from the same prohormone (proinsulin) as C-peptide requires administration 3-5 times daily.